Hydroxamic acid derivatives as proteinase inhibitors

ABSTRACT

Compounds of formula (I) are matrix metalloproteinase inhibitors wherein X represents a carboxylic acid group —COOH, or a hydroxamic acid group —CONHOH;R 2  represents a radical of formula (II): R 3 —(ALK) m —(Q) p —(ALK) n —, and W represents a cyclic amino radical of formula (IIIA) or (IIIB):

[0001] This invention relates to novel hydroxamic acid and carboxylicacid derivatives which are inhibitors of matrix metalloproteinases topharmaceutical compositions comprising such compounds and to their usein the treatment of diseases and conditions responsive to modulation ofmatrix metalloproteinase activity.

BACKGROUND TO THE INVENTION

[0002] The matrix metalloproteinases (MMPs) are a family of enzymesincluding interstitial collagenase, neutrophil collagenase,collagenase-3, 72 kDa gelatinase, 92 kDa gelatinase, stromelysin-1,stromelysin-2, stromelysin-3, matrilysin, macrophage metalloelastase,membrane-type metalloproteinase-1 and membrane-type metalloproteinase-2.These enzymes share a common zinc-containing catalytic domain and apro-sequence which maintains latency. A wide range of cells and tissuescan express MMPs in response to activation by inflammatory stimuli suchas interleukin-1 or tumour necrosis factor-α (TNF-α). Different stimulican induce overlapping yet distinct repertoires of MMPs and differentcell types can respond to the same stimuli by expression of distinctcombinations of MMPs. MMPs can degrade the protein components ofextracellular matrix such as collagens, vitronectin and elastin, andhave recently been shown to process membrane proteins such as pro-TNF-αto release soluble TNF-α. MMPs are thought to play a central role in thepathology of inflammatory diseases such as rheumatoid arthritis as wellas in the growth and metastasis of tumours.

[0003] Compounds which have the property of inhibiting the action ofMMPs are thought to be potentially useful for the treatment orprophylaxis of conditions involving such tissue breakdown, for examplerheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis,periodontitis, gingivitis, corneal epidermal venous, diabetic or gastriculceration, ulcerative colitis, Crohn's disease, pressure sores, andtumour metastasis, invasion and growth. MMP inhibitors are also ofpotential value in the treatment of neuroinflammatory disorders,including those involving myelin degradation, for example multiplesclerosis, as well as in the management of angiogenesis dependentdiseases which include arthritic conditions and solid tumour growth aswell as psoriasis, proliferative retinopathies, neovascular glaucoma,ocular tumours, angiofibromas and hemangiomas, cardiac and cerebralinfarction, and wound healing.

[0004] A known class of collagenase inhibitors is represented by thosedisclosed in EP-A-0574758 (Roche), EP-A-0684240 (Roche), and WO 95/33731(Roche). In general, the compounds disclosed in those publications maybe represented by the structural formula (IA):

[0005] in which R₁, R₂ and the N-containing ring are variable inaccordance with the specific disclosures of the publications.

[0006] Another known class of MMP inhibitors is represented by thosedisclosed in EP-A-0606046 (Ciba-Geigy) WO 96/00214 (Ciba-Geigy), WO95/35275 (British Biotech) and WO 95/35276 (British Biotech), which ingeneral may be represented by the structural formula (IB):

[0007] in which R₁, R₂ and and R₃ are variable in accordance with thespecific disclosures of the publications.

[0008] WO 99/24399 (Darwin Discovery Ltd), published May 20, 1999,discloses MMP inhibitors inter alia of structural formula (IC)

[0009] wherein X is —SO²— or—SO—, and R₁, R₂ and each B is as defined inthe document.

BRIEF DESCRIPTION OF THE INVENTION

[0010] The present invention makes available a new class of inhibitorsof MMPs which, as a result of that activity, are useful in themanagement of diseases or disorders associated with over production ofor over responsiveness to MMPs. The compounds of the invention differ instructure from those of WO 99/24399 inter alia in that the methylenegroup equivalent to that marked with an asterisk in formula (IC) issubstituted in the present compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0011] According to the present invention there is provided a compoundof formula (I)

[0012] wherein

[0013] X represents a carboxylic acid group —COOH, or a hydroxamic acidgroup—CONHOH;

[0014] R₂ represents a radical of formula (II)

R₃—(ALK)_(m)—(Q)_(p)—(ALK)_(n)—  (II)

[0015]  wherein

[0016] R₃ represents hydrogen or an optionally substituted cycloalkyl,optionally substituted cycloalkenyl, optionally substituted aryl, oroptionally substituted heterocyclic ring having 5 or 6 ring members,

[0017] each ALK independently represents an optionally substituteddivalent C₁-C₃ alkylene radical,

[0018] Q represents —O—, —S—, —S(O)—, —S(O₂)—, —C(O)O—, —OC(O)— or—N(R₉)— wherein R₉ is hydrogen, C₁-C₆alkyl, or C₁-C₆alkoxy, and

[0019] m, n and p are independently 0 or 1;

[0020] R₁ represents a radical of formula (II) as defined for R₂, exceptthat R₁ is not hydrogen;

[0021] W represents a cyclic amino radical of formula (IIIA) or (IIIB):

[0022]  wherein

[0023] Y represents —O—, —S—, —S(O)—, —S(O₂), —N(R₈)—, —(CH(R₈))—, or—(C═N-R₈)— wherein R₈ is a radical of formula (II) as defined inrelation to R₂; and

[0024] (i) R₄, R₅, R₆ and R₇ each independently represents a radical offormula (II) as defined in relation to R₂, and R_(4a) and R_(7a) eachindependently represent hydrogen or C₁-C₃ alkyl, or

[0025] (ii) R₄, R_(4a) and R₅ taken together with the carbon atoms towhich they are attached form an optionally substituted benzene orpyridine ring fused to the cyclic amine ring, R_(7a) represents hydrogenor C₁-C₃ alkyl, and R₆ and R₇ each independently represents a radical offormula (II) as defined in relation to R₂, or

[0026] (iii) R₄, R_(4a) and R₅ taken together with the carbon atoms towhich they are attached form an optionally substituted benzene orpyridine ring fused to the cyclic amine ring, R₆, R₇ and R_(7a) takentogether with the carbon atoms to which they are attached also form anoptionally substituted benzene or pyridine ring fused to the cyclicamine ring, or

[0027] (iv) when W is a cyclic amino radical of formula (IIIA) wherein Yis —(CH(R₈))—, then R₄ R_(4a) and R₈ taken together with the carbonatoms to which they are attached form an optionally substituted benzeneor pyridine ring fused to the cyclic amine ring, R_(7a) representshydrogen or C₁-C₃ alkyl, and R₅, R₆ and R₇ each independently representsa radical of formula (II) as defined in relation to R₁ and R₂, or

[0028] (v) when W is a cyclic amino radical of formula (IIIB) then R₄,R_(4a), R₇ and R_(7a) taken together with the carbon atoms to which theyare attached form an optionally substituted benzene or pyridine ringfused to the cyclic amine ring, and R₅ and R₆ each independentlyrepresents a radical of formula (II) as defined in relation to R₁ andR_(2,)

[0029] or a pharmaceutically acceptable salt, hydrate or solvatethereof.

[0030] As used herein the term “C₁-C₃alkyl” means a straight or branchedchain alkyl moiety having from 1 to 3 carbon atoms, including forexample, methyl, ethyl and n-propyl.

[0031] As used herein the term “divalent C₁-C₃alkylene radical” means asaturated hydrocarbon chain having from 1 to 3 carbon atoms and twounsatisfied valencies.

[0032] As used herein the term “cycloalkyl” means a saturated alicyclicmoiety having from 3-8 carbon atoms and includes, for example,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl andcyclooctyl.

[0033] As used herein the term “cycloalkenyl” means a saturatedalicyclic moiety having from 5-8 carbon atoms and at least one doublebond, and includes, for example, cyclopentenyl, cyclohexenyl,cycloheptenyl and cyclooctenyl.

[0034] As used herein the term “aryl” means a mono-, bi- or tri-cycliccarbocyclic aromatic group, and includes groups consisting of twocovalently linked monocyclic carbocyclic aromatic groups. Illustrativeof such groups are phenyl, biphenyl and napthyl.

[0035] As used herein, the term C₃-C₈ carbocyclic ring means a ring of 3to 8 carbon atoms, with no heteroatom as part of the ring. The termincludes aromatic (aryl) and non aromatic (non aryl) carbocyclic rings,for example the benzene ring and cycloalkyl rings.

[0036] As used herein the term “heteroaryl” refers to a 5- or 6-memberedaromatic ring containing one or more heteroatoms, and optionally fusedto a benzyl or pyridyl ring; and to groups consisting of two covalentlylinked 5- or 6-membered aromatic rings each containing one or moreheteroatoms; and to groups consisting of a monocyclic carbocyclicaromatic group covalently linked to a 5- or 6-membered aromatic ringscontaining one or more heteroatoms, Illustrative of such groups arethienyl, furyl, pyrrolyl, imidazolyl, benzimidazolyl, thiazolyl,pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl,oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,4-([1,2,3]-thiadiazoly4-yl)phenyl and 5-isoxazol-3-ylthienyl.

[0037] As used herein the terms “heterocyclic ring having 5 or 6 ringmembers” “heterocyclyl” or “heterocyclic” includes “heteroaryl” asdefined above, and in addition means a 5 or 6 membered aromatic ornon-aromatic heterocyclic ring containing one or more heteroatomsselected from S, N and O, and optionally fused to a benzene ring,including for example, pyrrolyl, furyl, thienyl, piperidinyl,imidazolyl, oxazolyl, thiazolyl, thiadiazolyl, pyrazolyl, pyridinyl,pyrrolidinyl, pyrimidinyl, morpholinyl, piperazinyl, indolyl,benzimidazolyl, maleimido, succinimido, phthalimido and1,3-dioxo-1,3-dihydro-isoindol-2-yl groups.

[0038] Where any group herein is referred to as “optionally substituted”this means the group may be unsubstituted or substituted with at leastone substituent selected from (C₁-C₃)alkyl, (C₁-C₃)alkoxy, oxo, phenyl,phenoxy, hydroxy, mercapto, (C₁-C₆)alkylthio, amino, halo (includingfluoro, chloro, bromo and iodo), trifluoromethyl, cyano, nitro, —COOH,—CONH_(2,) —COOR^(A), —NHCOR^(A), —CONHR^(A), —NHR^(A), NR^(A)R^(B), or—CONR^(A)R^(B) wherein R^(A) and R^(B) are independently (C₁-C₃)alkyl.

[0039] Salts of the compounds of the invention include physiologicallyacceptable acid addition salts for example hydrochlorides,hydrobromides, sulphates, methane sulphonates, p-toluenesulphonates,phosphates, acetates, citrates, succinates, lactates, tartrates,fumarates and maleates. Salts may also be formed with bases, for examplesodium, potassium, magnesium, and calcium salts.

[0040] There are at least two actual or potential chiral centres in thecompounds according to the invention because of the presence ofasymmetric carbon atoms. The presence of several asymmetric carbon atomsgives rise to a number of diastereomers with R or S stereochemistry ateach chiral centre. The invention includes all such diastereomers andmixtures thereof.

[0041] In the compounds of the invention:

[0042] X is a carboxylic acid group —COOH, or a hydroxamic acid group—CONHOH;

[0043] R₁ may be, for example, an optionally substituted C₁-C₆alkyl,phenyl, or phenyl(C₁-C₆alkyl)— group;

[0044] R₂ may be, for example hydrogen, or an optionally substitutedC₁-C₆alkyl, phenyl(C₁-C₆alkyl)-group, or an optionally substitutedheterocyclic group;

[0045] W may be, for example a radical of formula (IIIC), (IIID) or(IIIE)

[0046] wherein R₁₀ is as defined in relation to R₂ in formula (I), forexample an optionally substituted phenyl, biphenyl, phenyl(C₁-C₆alkyl)—,phenoxy, phenoxy(C₁-C₃)alkyl, or heterocyclic group;

[0047] Thus, examples of compounds of the invention include thosewherein

[0048] X is a carboxylic acid group —COOH, or a hydroxamic acid group—CONHOH;

[0049] R₁ is n-propyl, iso-propyl n-butyl, iso-butyl, benzyl,phenylethyl, 4-fluorobenzyl, or 4-fluorophenylethyl;

[0050] R₂ is hydrogen, n-propyl, n-butyl, iso-butyl, benzyl,phenylethyl, tetrahydropyranyl,1-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)propyl, or1-(phthalimido)-propyl;

[0051] W is a radical of formula (IIIC), (IIID), or (IIIE) wherein R₁₀is n-propyl, n-butyl or iso-butyl; or a phenyl, phenoxy, benzyl,phenylethyl, phenylpropyl, phenoxy, or phenoxymethyl group, any of whichmay be substituted in the phenyl ring, for example in the 4-position, bychloro, fluoro, methoxy or cyano; pyridinyl or pyridinyloxy either ofwhich may be substituted by chloro, fluoro, methoxy or cyano; orbiphenyl or 4-pyridinylphenyl, either of which may be substituted ineither ring by chloro, fluoro, methoxy or cyano. Examples of W radicalsinclude 4-phenylmethylpiperidinyl, 4 methylpiperidinyl,4-(4-methylphenyl)piperidinyl, 4-(4-chlorophenoxy)piperidinyl,4-phenylpiperidinyl, 4(4-fluorophenyl)piperidinyl,4-(4-fluorophenoxy)piperidinyl, 4-(4-pyridinyloxy)-piperidinyl,4-(4-cyanophenyloxy)piperidinyl, 4-(4-cyanophenoxyimino)-piperdinyl,4-(4′-chloro-biphenyl4-yl)-piperdinyl, 4-(2-chloro-biphenyl4-yl)piperdinyl, 4-(4-fluorophenylmethyl)piperidinyl,4-(4-fluorophenoxymethyl)-piperidinyl, 4-phenylpiperazinyl,4-(4-fluorophenyl)piperazinyl, 4-(4-pyridinyl-methyl)piperazinyl,4-(4-chlororophenyl)piperazinyl, 4-pyridin4-ylpiperazinyl,4-phenylmethylpiperazinyl, and 4-(4-fluorophenylmethyl)piperazinyl.

[0052] Specific examples of compounds in accordance with the inventioninclude those named and characterised in the Examples herein, andpharmaceutically acceptable salts, hydrates or solvates thereof. Oneinteresting compound of the invention is3-[4-(4-fluoro-phenoxymethyl)-piperidine-1-sulfonyl]-N-hydroxy4-phenyl-butyramide,and its pharmaceutically acceptable salts, hydrates and solvates. Thiscompound is an inhibitor of collagenase-3 (MMP-13), in particular.Another interesting compound of the invention is3-(4-benzyl-piperidine-1-sulfonyl)-N-hydroxy4-phenyl-butyramide, and itspharmaceutically acceptable salts, hydrates and solvates. This compoundis an inhibitor of gelatinase A, in particular.

[0053] Compounds of the invention wherein X is a hydroxamic acid groupmay be prepared by a process which comprises causing a carboxylic acidof the invention of general

[0054] or an activated derivative thereof to react with hydroxylamine,O-protected hydroxylamine, N,O-diprotected hydroxylamine, or a saltthereof, W, R₁ and R₂ being as defined in general formula (I), andsubsequently removing any protecting groups from the hydroxylaminemoiety

[0055] Conversion of (IV) to an activated derivative such as thepentafluorophenyl, hydroxysuccinyl, or hydroxybenzotriazolyl ester maybe effected by reaction with the appropriate hydroxy compound in thepresence of a dehydrating agent such as dicyclohexyl dicarbodiimide(DCC), N,N-dimethylaminopropyl-N′-ethyl carbodiimide (EDC), or2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ).

[0056] Examples of O-protected hydroxylamines for use in the process ofthe invention above include O-benzylhydroxylamine,O-4-methoxybenzylhydroxylamine, O-trimethylsilylhydroxylamine, andO-tert-butoxycarbonylhydroxylamine.

[0057] Examples of O,N-diprotected hydroxylamines for use in the processof the invention include N,O-bis(benzyl)hydroxylamine,N,O-bis(4-methoxybenzyl)hydroxylamine,N-tert-butoxycarbonyl-O-tert-butyidimethylsilylhydroxylamine,N-tert-butoxycarbonyl-O-tetrahydropyranylhydroxylamine, andN,O-bis(tert-butoxycarbonyl)hydroxylamine.

[0058] Carboxylic acids of formula (IV) may be prepared by condensationof a sulfinyl chloride of formula (V) or a sulfonyl chloride of formula(VA)

[0059] wherein V is a carboxyl protecting group and R₁ and R₂ are asdefined with respect to formula (I), with a cyclic amine W-H wherein Wis as defined with respect to formula (I) followed, in the case of thesulfinyl chloride (V), by oxidation of the sulfinyl group to a sulfonylgroup and, in each case, thereafter removing the protecting group V.

[0060] Sulfinyl chlorides of formula (V) may be prepared by reaction ofan acetylthio compound of formula (VI)

[0061] wherein V is a carboxyl protecting group and R₁ and R₂ are asdefined with respect to formula (I), with sulfuryl chloride in thepresence of acetic anhydride.

[0062] Sulfonyl chlorides of formula (VA) may be prepared by reaction ofan acetylthio compound of formula (VI) as defined above, with chlorineand aqueous acetic acid.

[0063] Acetylthio compounds of formula (VI) may be prepared by reactionof an α,β-unsaturated carboxylic acid of formula (VII)

[0064] wherein R₁ and R₂ are as defined with respect to formula (I),withthiolacetic acid, followed by protection of the carboxylic acid group.

[0065] The preparative Examples herein give further details of thereaction conditions for the preparation of compounds of the inventionand intermediates there of.

[0066] As mentioned above, the compounds of the invention are inhibitorsof matrix metalloproteinases and therefore of value in the treatment ofdisease states or conditions resulting from over production of, or overresponsiveness to, MMPs.

[0067] Accordingly in another aspect, this invention concerns:

[0068] (i) a method of treatment of conditions in mammals, in particularin humans, resulting from over production of or over responsiveness toMMPs, which method comprises administering to the mammal an effectiveamount of a compound as defined with respect to formula (I) above; and

[0069] (ii) a compound as defined with respect to formula (I) for use inhuman or veterinary medicine treatment of conditions resulting from overproduction of or over responsiveness to MMPs; and

[0070] (iii) the use of a compound as defined with respect to formula(I) in the preparation of an agent for treatment of conditions inmammals, in particular in humans, resulting from over production of orover responsiveness to MMPs.

[0071] Conditions resulting from over production of or overresponsiveness to MMPs include rheumatoid arthritis, osteoarthritis,osteopenias such as osteoporosis, periodontitis, gingivitis, corneal.Epidermal, venous, diabetic or gastric ulceration, ulcerative colitis,Crohn's disease, pressure sores, tumour metastasis, invasion and growth,multiple sclerosis, angiogenesis dependent diseases, which includearthritic conditions and solid tumour growth as well as psoriasis,proliferative retinopathies, neovascular glaucoma, ocular tumours,angiofibromas and hemangiomas.

[0072] According to a further aspect of the invention there is provideda pharmaceutical or veterinary formulation comprising a compound ofgeneral formula (I) and a pharmaceutically and/or veterinarilyacceptable carrier. One or more compounds of general formula (I) may bepresent in association with one or more non-toxic pharmaceuticallyand/or veterinarily acceptable carriers and/or diluents and/or adjuvantsand if desired other active ingredients.

[0073] Compositions with which the invention is concerned may beprepared for administration by any route consistent with thepharmacokinetic properties of the active ingredient(s).

[0074] Orally administrable compositions may be in the form of tablets,capsules, powders, granules, lozenges, liquid or gel preparations, suchas oral, topical, or sterile parenteral solutions or suspensions.Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricant, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants for example potato starch, or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods well known in normal pharmaceutical practice. Oralliquid preparations may be in the form of, for example, aqueous or oilysuspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example sorbitol,syrup, methyl cellulose, glucose syrup, gelatin hydrogenated ediblefats; emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters such asglycerine, propylene glycol, or ethyl alcohol; preservatives, forexample methyl or propyl p-hydroxybenzoate or sorbic acid, and ifdesired conventional flavouring or colouring agents.

[0075] For topical application to the skin, the active ingredient(s) maybe made up into a cream, lotion or ointment. Cream or ointmentformulations which may be used for the drug are conventionalformulations well known in the art, for example as described in standardtextbooks of pharmaceutics such as the British Pharmacopoeia.

[0076] For treatment of the respiratory tract, the active ingredient(s)may be made up as inhaleable aerosols or sprays in which the compound isdissolved or suspended, or as inhaleable powders, by conventionalformulation methods.

[0077] The active ingredient(s) may also be administered parenterally ina sterile medium. Depending on the vehicle and concentration used, thedrug can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as a local anaesthetic, preservative andbuffering agents can be dissolved in the vehicle.

[0078] Safe and effective dosages for different classes of patient andfor different disease states will be determined by clinical trial as isrequired in the art. It will be understood that the specific dose levelfor any particular patient will depend upon a variety of factorsincluding the activity of the specific compound employed, the age, bodyweight, general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

[0079] The following Examples illustrate embodiments of the invention.The starting α,β-unsaturated acids are either commercially available ormay be prepared by known literature methods. In the Examples, thefollowing abbreviations have been used: DCM Dichloromethane DMAP4-Dimethylaminopyridine DMF N,N-Dimethylformamide EDCN-Ethyl-N¹-(3-dimethylaminopropyl) carbodiimide hydrochloride EtOAcEthylacetate EtOH Ethanol HOBt 1-Hydroxybenzotriazole MeOH MethanolNalO₄ Sodium periodate NaOH Sodium hydroxide NMM N-Methyl morpholinePh₃PO Triphenyl phospine oxide RuCl₃.xH₂O Ruthenium (III) chloridehydrate TEA Triethylamine TFA Trifluoroacetic acid TLC Thin layerchromatography

[0080]¹H and ¹³C NMR spectra were recorded using either a Bruker DPX250spectrometer at 250.1 and 62.9 MHz respectively, or a Bruker AMX2 500spectrometer at 500.1 and 125.7 MHz respectively. Mass spectra wereobtained on a PE-SCIEX API 165 with a turbo ion spray interface. Infrared spectra were obtained on a Perkin Elmer 1600 series FTIR machine.All organic solutions were dried over MgSO₄.

EXAMPLE 1

[0081]

3-(4-Benzy-piperidine-1-sulfonyl)-4-phenyl-butyric acid.

[0082] STEP A:

[0083] 5-Phenyl-but-2-enoic acid

[0084] Tert-butoxycarbonylmethylene triphenyl phosphonium bromide (22.16g, 48.5 mmol) was suspended in water (100 mL) and DCM (50 mL) andbasified with 2M NaOH (against phenolphthalein indicator). The layerswere separated and the aqueous layer re-extracted with DCM. The DCMextracts were combined, dried, filtered and evaporated under reducedpressure to give a gummy solid. This was re-suspended in benzene (50 mL)with stirring and cooled to 0° C. Phenylacetaldehyde (5.76 g, 48 mmol)was added and the reaction warmed to room temperature and stirredovernight. The precipitated Ph₃PO was filtered off and the filtrateconcentrated in vacuo. The resulting residue was stirred in hexanes andre-filtered. The filtrate was again concentrated under reduced pressureto give 3-(4-Benzy-piperidine-1-sulfonyl)-4-phenyl-butyric acidtert-butyl ester as a yellow oil (8.29 g, 38 mmol). This was taken up inDCM with stirring and cooled to 0° C. TFA (10 mL) was added and thereaction placed in the fridge overnight. The solvents were evaporatedunder reduced pressure to give the title compound as a semi-solid (6.66g, Quant.) ¹H-NMR δ (CDCl₃) 7.48-7.16 (6H, m), 5.79 (1H, d, J=15.6 Hz),3.55 (2H, d, J=6.7 Hz).

[0085] STEP B:

[0086] 3-Acetylsulfanyl-4-phenyl-butyric acid.

[0087] Thiolacetic acid (9.3 mL, 131 mmol) was added to4-phenyl-but-2-enoic acid (4.25 g, 26.2 mmol) under an argon atmoshere.The resulting solution stirred with the exclusion of light at roomtemperature for 48 h. The solvent was evaporated to yield an orange oil(6.26 g, Quant). ¹H-NMR δ (CDCl₃), 7.25 (5H, m), 4.09 (1H, m), 2.99 (2H,d, J=6.4 Hz), 2.66(2H, d, J=6.4 Hz) and 2.30 (3H, s).

[0088] STEP C:

[0089] 3-Acetylsulfanyl-4-phenyl-butyric acid benzyl ester.

[0090] The product from Step B (5.4 g, 26.2 mmol) was taken up in DCM(50 mL) with stirring and cooled to 0° C. EDC (6.0 g, 31.4 mmol) andDMAP (164 mg, 1.31 mmol) were added followed by benzyl alcohol (2.4 mL,23.6 mmol). The resulting solution was stirred at room temperatureovernight with the exclusion of moisture. The reaction was diluted withDCM and washed successively with 1 M HCl, water, 5% Na₂CO₃ solution,brine and dried, filtered and evaporated to give a dark oil. This waspurified by silica gel column chromatography eluting with hexane/ethylacetate 1:1 to give the product as an orange oil (5.98 g, 70%). ¹H-NMR δ(CDCl₃) 7.38-7.17 (10H, m); 5.11 (2H, s), 4.08 (1H, m), 2.96 (2H, d,J=6.4 Hz), 2.64 (2H, d, j=6.4 Hz) and 2.27 (3H, s).

[0091] STEP D:

[0092] 3-(4-Benzyl-piperidine-1-sulfinyl)-4-phenyl-butyric acid benzylester.

[0093] The product from Step C (670 mg, 2.05 mmol) was taken up in dryDCM (5 mL) with stirring and cooled to −15° C. under argon atmosphere.Acetic anhydride (193 μL, 2.05 mmol) and sulfuryl chloride (329 μL, 4.1mmol) were added via a syringe. After being stirred for 1 h, the mixturewas concentrated in vacuo at room temperature. The sulfinyl chloridethus obtained was used for coupling without purification. A solution of4-benzyl piperidine (370 μL, 2.11 mmol) in dry DCM (5 mL) and NMM (232μL, 2.11 mmol) was added via a cannular to a stirred solution of thesulfinyl chloride in dry DCM (10 mL) at 0° C. under an argon atmosphere.The mixture was allowed to warm to room temperature and stirredovernight. The solvent was evaporated to give an oil which was purifiedby silica gel column chromatography eluting with hexane/ethyl acetate1:1. This gave the product as a mixture of diastereoisomers (430 mg,44%). ¹H-NMR δ (CDCl₃) 7.38-7.08 (15H, m), 5.05 (2H, m), 3.55 (1H, m),3.41-3.25 (2H, m), 3.01-2.42 (7H, m), 1.67 (1H, m) and 1.26 (2 H, m).

[0094] STEP E:

[0095] 3-(4-Benzyl-piperidine-1-sulfonyl)-4-phenyl-butyric acid benzylester.

[0096] The product from Step D (430 mg, 0.91 mmol) was taken up inacetonitrile (1.5 mL) with stirring and cooled to 0° C. RuCl₃.3H₂O (0.5mg) and NalO₄ (290 mg, 1.37 mmol) were added followed by water (2 mL).The resulting mixture was stirred at room temperature for 2½h until tic(hex/EtOAc 1:1) indicated the absence of starting material. The reactionwas diluted with DCM, the layers separated and the aqueous layer wasfurther extracted with DCM. The organic extracts were combined, dried,filtered and concentrated in vacuo to give the product as an oil (360mg, 81%). ¹H-NMR δ (CDCl₃) 7.37-7.09 (15H, m), 4.96 (1H,d, J=12.2Hz),4.94 (1H, d, j=12.2 Hz), 3.91 (1H, m), 3.89-3.68 (2H, m), 3.31 (1H, dd,J=4.5, 14.0 Hz), 2.88-2.45 (7H, m), 1.72-1.50 (3H, m) and 1.29-1.15 (2H,m)

[0097] STEP F:

[0098] 3-(4-Benzyl-piperidine-1-sulfonyl)-4-phenyl-butyric acid.

[0099] The product from Step E (360 mg, 0.73 mmol) was taken up in EtOAc(10 mL) with stirring under a blanket of argon. 10% palladium oncharcoal (130 mg) was added. The resulting suspension was hydrogenatedin a PARR apparatus at room temperature overnight.The system was purgedwith argon and the catalyst removed by filtration. The filtrate wasevaporated under reduced pressure to give the desired product as a gum(292 mg, Quant). ′H-NMR δ(MeOD) 7.24-7.10 (10H, m), 3.89 (1H, m), 3.69(2H, m), 3.25 (1H, dd, J =4.8, 17.1 Hz), 2.81-2.64 (4H, m), 2.53 (2H, d,j=6.7 Hz), 2.45 (1H, dd, J=4.8, 17.1 Hz), 1.61 (3H, m) and 1.28 (2H, m).¹³C-NMR δ(MeOD) 174.3, 141.7, 138.8, 130.8, 130.6, 130.2, 129.7, 128.4,127.4, 61.0, 47.6, 44.2, 39.2, 36.6, 34.8, 33.7. ESMS=(M+1)402.2,(M−1)400.0.

EXAMPLE 2

[0100]

3-(4-Benzyl-piperidine-1-sulfonyl)-N-Hydroxy4-phenyl-butyramide.

[0101] STEP G:

[0102] 3-(4-Benzyl-piperidine-1-sulfonyl)-N-Hydroxy-4-phenyl-butyramide.

[0103] The product from Step F (292 mg, 0.73 mmol) was taken up in DMF(5 mL) with stirring and cooled to 0° C. and HOBt (124 mg, 0.92 mmol)followed by EDC (176 mg, 0.92 mmol) were added. After 1 h at 0° C.hydroxylamine hydrochloride (161 mg, 2.31 mmol) and NMM (254 μL, 2.31mmol) were added. The reaction was allowed to warm to room temperatureand stirred overnight. The solvent was removed in vacuo and the residuewas purified by reverse phase HPLC to give the desired product as awhite solid (21 mg). ′H-NMR δ(MeOD) 7.33-7.11 (10H, m), 4.00 (1H, m),3.68 (2H, m), 3.23 (1H, dd, J=4.9, 14.1 Hz), 2.76 (3H, m), 2.51 (3H, m),2.21 (1H, dd, J-4.9, 14.1 Hz), 1.63 (3H, m) and 1.20 (2H, m). ¹³C-NMRδ(MeOD) 169.5, 141.7, 138.9, 130.8, 130.6, 130.2, 129.7, 128.4, 127.4,60.0, 47.4, 44.2, 39.2, 36.7, 33.6, 33.3. IR v_(max) (reflection disc)2921, 1665, 1447, 1309, 1137, 940, 747. ESMS=(M+1)417.0, (M+TFA−1)529.2, (M−1) 415.0.

[0104] The compounds of Examples 3 to 18 were prepared by modificationof the methods described for Examples 1 and 2 as indicated in the text.The starting α,β-unsaturated acids if not commercially available maybeprepared from commercially available aldehydes and ylides as describedin Step A. The substituted piperidine derivatives or other aminesrequired are either commercially available or may be prepared by knownliterature methods (Perregaard, J; Moltzen, E. K; Meier, E; Sanchez, C;J. Med. Chem. 1995, 38, 1998-2008 and by using the Mitsonobu reactionconditions in Gowravaram, M. R; Tomczuk, B. E; Johnson, J. S; Delecki,D; Cooke, E. R; Ghose, A. K; Mathiowetz, A. M; Spurlino, J. C; Rubin, B;Smith, D. L; Pulvino, T; Wahl, R. C; J. Med. Chem. 1995, 38, 2570-2581).

EXAMPLE 3

[0105]

3-(4-Methyl-piperidine-1-sulfonyl)-4-phenyl-butyric acid

[0106] STEP H:

[0107] 3-Chlorosulfonyl-4-phenyl-butyric acid benzyl ester

[0108] The product from Step C (1.20 g, 3.66 mmol) was suspended in a 5%acetic acid water solution (50 mL) with stirring and cooled to 0° C.Chlorine gas was bubbled through this cooled suspension for 15 min.Reaction was stirred at 0° C. was a further 20 min and then the excesschlorine was removed by bubbling argon through the suspension. theproduct was extracted into DCM. The DCM extract was was washed withwater (×3), brine (×3), dried, filtered and evaporated in vacuo to givethe title compound as a yellow oil (0.92 g, 2.6 mmol). ¹H-NMR δ (CDCl₃)7.42-7.20 (10H, m), 4.98 (2H,s), 4.45 (1H, m), 3.62 (1H, dd, J=4.4, 14.1Hz), 3.12 (1H, dd, J=5.9, 17.1 Hz), 3.00 (1H, dd, J=10, 14.1Hz) and 2.73(1H, dd, J=6.2, 17.1 Hz)

[0109] STEP I:

[0110] 3-(4-Methyl-piperidine-1-sulfonyl)-4-phenyl-butyric acid benzylester

[0111] The product from Step H (0.92 g, 2.6 mmol) was taken up in DCM(25 mL) with stirring and cooled to 0° C. TEA (362 μL, 2.6 mmol) and4-methyl-piperidine (307 μL, 2.6 mmol) were added and the reactionwarmed to room temperature and stirred overnight. The reaction wasdiluted with DCM and washed successively with water, 1M HCl, water,brine, dried, filtered and concentrated in vacuo to give a yellow oil.This was purified by silica gel column chromatography eluting withhex/EtOAc 8:2 to give the titled compound as a yellow oil (440 mg, 41%).¹H-NMR δ (CDCl₃) 7.40-7.18 (10H, m), 5.0 (1H, d, J=12.2 Hz), 4.95 (1H,d, J=12.2 Hz), 3.9 (1H, m), 3.79-3.68 (2H, m), 3.42-3.31 (1H, dd, J=4.4,14.1 Hz), 2.91-2.80 (1H, dd, J=5.9, 17.1 Hz), 2.79-2.62 (3H, m),2.58-2.47 (1H, dd, J=6.2, 17.1 Hz), 1.69-135 (2H, m), 1.30-1.10 (3H, m)and (3H, d, J=6.2 Hz).

[0112] STEP J:

[0113] 3-(4-Methyl-piperidine-1-sulfonyl)-4-phenyl-butyric acid

[0114] The product from Step I (440 mg, 1.06 mmol) was converted to thetitle compound using the method in Step F using MeOH (10 mL) as thereaction solvent. Oil (270 mg, 78%). ′H-NMR δ(MeOD) 7.29 (5H, m), 3.88(1H, m), 3.67 (2H, m), 3.23 (1H, dd, J=4.3, 12.8 Hz), 2.84 (4H, m), 2.45(1H, dd, J=4.3, 12.8 Hz), 1.63 (2H, m), 1.47 (1H, m), 1.17 (2H, m) and0.93 (3H, d, J=6.4 Hz). ¹³C-NMR δ(MeOD) 174.2, 138.8, 130.8, 130.2,128.4, 61.0, 47.6, 36.6, 35.7, 34.7, 32.0, 22.5. ESMS=(M+Na) 348.2,(M−1) 323.8.

EXAMPLE 4

[0115]

N-Hydroxy-3-(4-Methylpiperidine-1-sulfonyl)-4-phenyl-butyramide.

[0116] The product from Step J (270 mg, 0.83 mmol) was converted to thetitle compound using the method in Step G to give the title compound asa pink gum (129 mg). ′H-NMR δ(MeOD) 7.31 (5H, m), 3.97 (1H, m), 3.63(2H, m), 3.24 (1H, dd, J=4.9, 14.2 Hz), 2.79 (3H, m), 2.51 (1H, dd,J=7.5, 15.6 Hz), 2.26 (1H, dd, J=4.9, 14.2 Hz), 1.60 (2H, m), 1.46 (1H,m), 1.14 (2H, m) and 0.92 (3H, d, J=6.39 Hz). ¹³C-NMR δ(MeOD) 169.5,138.9, 130.7, 130.1, 128.4, 59.9, 47.4, 36.7, 35.7, 33.3, 32.0, 22.5.ESMS=(M+Na) 363.0, (M−1) 338.8.

EXAMPLE 5

[0117]

3-[4-(4-Fluoro-phenoxymethyl)-piperidine-1-sulfonyl]-4-phenyl-butyricacid

[0118] Pink gum. ′H-NMR δ(MeOD) 7.35-7.20 (5H, m), 7.12-6.84 (4H, m),3.91 (1H, m), 3.79-3.76 (4H, m), 3.31 (1H, m), 2.90-2.66 (4H, m),2.49-2.41 (1H, dd, J=4.4, 17.2 Hz), 2.0-1.70 (3H, m) and 1.43-1.22 (2H,m). ¹³C-NMR δ(MeOD) 174.3, 160.9, 157.1, 138.8, 130.8, 130.2, 128.5,117.2, 117.1, 116.9, 116.8, 74.2, 61.1, 47.2, 37.3, 36.6, 34.8, 30.5. IRv_(max) (reflection disc) 2947, 1730, 1598, 1503, 1409,1253, 1054, 1030,948, 829, 699. ESMS=(M+1) 436.0, (M+TFA−1) 548.0, (M−1) 433.8.

EXAMPLE 6

[0119]

3-[4-(4-Fluoro-phenoxymethyl)-piperidine-1-sulfonyl]-N-hydroxy-4-phenyl-butyramide

[0120] Pale pink foam. ′H-NMR δ(MeOD) 7.40-7.26 (5H, m), 7.01-6.84 (4H,m), 4.13 (1H, m), 3.78-3.72 (4H, m), 3.24 (1H, m), 2.81-2.74 (3H, m),2.59-2.50 (1H, dd, J=7.6, 15.7 Hz), 2.30-2.22 (1H, dd, J=4.4, 15.7 Hz),2.02-1.80 (3H, m) and 1.47-1.20 (2H, m). ¹³C-NMR δ(MeOD) 169.5, 160.9,157.1, 138.9, 130.7, 130.2, 128.4,117.2, 117.1, 117.0, 116.8, 74.2,60.0, 47.0, 37.3, 36.6, 33.3, 30.5. IR v_(max) (reflection disc) 3293,2919, 1664, 1503, 1449, 1307, 1208, 1136, 1044, 937, 828, 751.ESMS=(M+Na) 473.2, (M+TFA−1) 563.2.

EXAMPLE 7

[0121]

4-Phenyl-3-(4-phenyl-piperazine-1-sulfonyl)-butyric acid; compound withtrifluoro-acetic acid.

[0122] Pale pink foam. ′H-NMR δ(MeOD) 7.50-7.20 (7H, m), 7.20-6.99 (3H,m), 4.01 (1H, m), 3.50 (4H, m), 3.40-3.20 (5H, m), 2.89-2.80 (1H, dd,J=7.3, 17.2 Hz), 2.80-2.71 (1H, dd, J=7.3, 17.2 Hz) and 2.54-2.46 (1H,dd, J=4.3, 17.2 Hz). ¹³C-NMR δ(MeOD) 174.2, 150.2, 138.7, 131.0, 130.8,130.3, 128.6, 124.7, 119.6, 61.2, 52.8, 46.7, 36.4, 34.8. IR v_(max)(reflection disc) 3030, 1726, 1661, 1494, 1442, 1324, 1267, 1143, 942.ESMS=(M+1) 388.8, (M−1) 387.0.

EXAMPLE 8

[0123]

N-Hydroxy4-phenyl-3-(4-phenyl-piperazine-1-sulfonyl)-butyramide;compound with trifluoro-acetic acid.

[0124] Pink foam. ′H-NMR δ(MeOD) 7.33-7.23 (7H, m), 7.10-6.96 (3H, m),4.09 (1H, m), 3.42-3.36 (5H, m), 3.29 (4H, m), 2.88-2.78 (1H, dd, J=8,16 Hz), 2.62-2.52 (1H, dd, J=8, 16 Hz) and 2.33-2.25 (1H, dd, J=4.3, 16Hz). ¹³C-NMR δ(MeOD) 169.6, 150.2, 138.7, 131.0, 130.8, 130.3, 128.6,124.9, 119.7, 60.1, 52.8, 46.8, 36.3, 33.3. IR V_(max) (reflection disc)3189, 1668, 1493, 1446, 1143, 945. ESMS=(M+1) 404.0, (M−1) 402.0.

EXAMPLE 9

[0125]

3-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]4-phenyl-butyric acid

[0126] White solid. ′H-NMR δ(MeOD) 7.45-7.19 (7H, m), 7.03-6.97 (2H, m),3.99 (1H, m), 3.87-3.81 (2H, bm), 3.37 (1H, m), 3.0-2.60 (5H, m), 2.50(1H, dd, J=4.1, 17.2 Hz), 1.90-1.79 (2H, m) and 1.73-1.56 (2H, m).¹³C-NMR δ(MeOD) 174.3, 165.2, 161.4, 143.1, 138.8, 130.8, 130.2, 130.0,129.8, 128.5, 116.6, 116.3, 61.0, 47.9, 42.9, 36.6, 35.0, 34.9.ESMS=(M+Na) 428.2, (M−1) 404.0.

EXAMPLE 10

[0127]

3-[4-(4-Fluoro-phenyl)-piperidine-1-sulfonyl]-N-hydroxy-4-phenyl-butyramide

[0128] White solid. ′H-NMR δ(MeOD) 7.40-7.20 (7H, m), 7.22-6.96 (2H, m),4.05 (1H, m), 3.81-3.77 (2H, bm), 3.30 (1H, m), 3.02-2.85 (3H, bm),2.77-2.55 (2H, bm), 2.30-2.34 (1H, bdd), 1.90-1.80 (2H, m) and 1.75-1.55(2H, m). ¹³C-NMR δ(MeOD) 169.5, 165.2, 161.4, 143.2, 139.0, 130.8,130.2, 130.0, 129.9, 128.4, 116.6, 116.2, 59.9, 47.7, 47.6, 43.0, 36.6,35.0, 34.9, 33.4. IR v_(max) (ATR) 2922, 1653, 1508, 1448, 1306, 1218,1134, 1050, 939, 823, 739, 699. ESMS=(M+Na) 443.0, (M+TFA−1) 533.2,(M−1) 418.8.

[0129] In examples 11-18 a tert-butyl ester was used in place of thebenzyl ester (Step C). The method for its preparation is described (StepK) and Step L replaces Step F.

EXAMPLE 11

[0130]

3-(4-Benzy-piperidine-1-sulfonyl)-5-phenyl-pentanoic acid

[0131] STEP K:

[0132] 3-Acetylsulfanyl-5-phenyl-pentanoic acid tert-butyl ester

[0133] 3-Acetylsulfanyl-5-phenyl-pentanoic acid was taken up in DCM (15mL) with stirring in a pressure bottle. c.H₂SO₄ (1 mL) was added and thesolution cooled to −78° C. Isobutylene gas was bubbled through thissolution until the volume had doubled. The pressure vessel was sealedand allowed to warm to room temperature and stirred overnight. Thereaction was re-cooled to −78° C. and opened and warmed to roomtemparature. The excess isobuylene gas was allowed to evaporate and thenthe reaction solution was poured into a stirred 1 M Na₂CO₃ solution. Theproduct was extracted into DCM and washed with brine, dried and filteredand evaporated under reduced pressure to give an orange oil (10.64 g,34.5 mmol). ¹H-NMR δ (CDCl₃) 7.27-7.14 (5H, m), 3.88 (1H, m), 2.80-2.51(4H, m), 2.34 (3H, s), 1.97-1.84 (2H, m) and 1.43 (9H, s).

[0134] STEP L;

[0135] 3-(4-Benzy-piperidine-1-sulfonyl-5-phenyl-pentanoic acid

[0136] 3-(4-Benzy-piperidine-1-sulfonyl)-5-phenyl-pentanoic acidtert-butyl ester (1.04 g, 2.2 mmol) was taken up in DCM (5 mL) withstirring and cooled to 0° C. TFA (5 mL) was added slowly and theresulting solution placed in the fridge overnight. Solvents evaporatedunder reduced pressure to give the title compound as a yellow oil (913mg, Quant). ′H-NMR δ(MeOD) 7.56-7.11 (10H, m), 3.66-3.56 (3H, m),2.90-2.59 (6H, m), 2.51 (2H, d, J=6.7 Hz), 2.20 (1H, m), 1.90 (1H, m),1.62-1.47 (3H, m) and 1.25-1.11 (2H, m). ¹³C-NMR δ(MeOD) 174.5, 142.6,141.7, 130.6, 130.1, 130.0, 129.7, 127.7, 127.4, 58.7, 47.6, 44.2, 39.2,35.5, 33.9, 33.7, 33.0. IR v_(max) (ATR) 2915, 1709, 1451, 1304, 1133,1041, 937, 746, 698. ESMS=(M+1) 416.0, (M−1) 414.0.

EXAMPLE 12

[0137]

3-(4-Benzy-piperidine-1-sulfonyl)-5-phenyl-pentanoic acid hydroxyamide

[0138] Off-white foam. ′H-NMR δ(MeOD) 7.40-7.13 (10H, m), 3.66-3.50 (3H,m), 2.88-2.58 (5H, m), 2.52 (2H, d, J=6.7 Hz), 2.39 (1H, dd, J=6.7, 15.3Hz), 2.10 (1H, m), 1.89 (1H, m), 1.79-1.47 (3H, m) and 1.22-1.08 (2H,m). ¹³C-NMR δ(MeOD) 169.6, 142.8, 141.7, 130.6, 130.1, 130.0, 129.7,127.7, 127.4, 58.1, 47.6, 44.2, 39.2, 34.2, 33.9, 33.7, 33.1. IR v_(max)(ATR) 2917, 1655, 1451, 1303, 1134, 1042, 937, 746, 698. ESMS=(M+1)431.2, (M−1) 429.0, (M+TFA−1) 543.0.

EXAMPLE 13

[0139]

3-(4-Methyl-piperidine-1-sulfonyl)-5-phenyl-pentanoic acid

[0140] Tan solid. ′H-NMR δ(MeOD) 7.51-7.15 (5H, m), 3.80-3.51 (3H, m),2.95-2.60 (6H, m), 2.17 (1H, m), 1.90 (1H, m), 1.81-1.61 (2H, m), 1.45(1H, m), 1.30-0.99 (2H, m), 0.92 (3H, d, J=6.5 Hz). ¹³C-NMR δ(MeOD)174.5, 142.6, 130.0, 127.7, 58.7, 47.7, 35.7, 35.5, 33.9, 33.0, 32.1,22.5. IR v_(max) (ATR) 2924, 2866, 1710, 1453, 1301, 1161, 1132, 1049,927, 747, 699. ESMS=(M+Na) 362.2, (M−1) 338.2.

EXAMPLE 14

[0141]

3-(4-Methyl-piperidine-1-sulfonyl)-5-phenyl-pentanoic acid hydroxyamide

[0142] Yellow oil. ′H-NMR δ(MeOD) 7.31-7.17 (5H, m), 3.70-3.61 (3H, m),2.88-2.61 (5H, m), 2.40 (1H, dd, J=6.9, 15.3 Hz), 2.13 (1H, m), 1.89(1H, m), 1.66-1.56 (2H, 1.48 (1H, m), 1.22-1.03 (2H, m) and 0.93 (3H, d,J=6.5 Hz). ¹³C-NMR δ(MeOD) 169.5, 142.8, 130.0, 127.7, 58.1, 47.6, 35.7,34.2, 33.9, 33.1, 32.1, 22.5. IR v_(max) (ATR)2922, 1655, 1438, 1302,1161, 1134, 1049, 928, 747, 695. ESMS=(M+Na) 377.2, (M−1) 353.2.

EXAMPLE 15

[0143]

3-(4-Benzyl-piperidine-1-sulfonyl)-5-methyl-hexanoic acid

[0144] Yellow oil. ′H-NMR δ(MeOD) 7.45-7.13 (5H, m), 3.84-3.60 (2H, m),3.59 (1H, m), 2.91-2.72 (2H, m), 2.68-2.46 (4H, m), 1.82-1.63 (5H, m),1.50 (1H, m), 1.39-1.03 (2H, m), 0.96 (3H, d, J=6.2 Hz) and 0.91 (3H, d,J=6.2 Hz). ¹³C-NMR δ(MeOD) 174.6, 141.7, 130.5, 129.7, 127.5, 58.2,47.9, 47.7, 44.2, 39.8, 39.3, 35.9, 33.7, 27.0, 23.9, 22.3. IR v_(max)(ATR) 2924, 1709, 1449, 1320, 1128, 1042, 937, 747, 699. ESMS=(M+Na)390.0, (M−1) 366.0.

EXAMPLE 16

[0145]

3-(4-Benzyl-piperidine-1-sulfonyl)-5-methyl-hexanoic acid hydroxyamide

[0146] Off-white foam. ′H-NMR δ(MeOD) 7.28-7.13 (15H, m), 3.72-3.59 (3H,m), 2.84-2.75 (2H, m), 2.69-2.59 (3H, m), 2.24 (1H, dd, J=6.1, 15.6 Hz),1.79-1.64 (5H, m), 1.45 (1H, m), 1.36-1.12 (2H, m) 0.94 (3H, d, J=6.3Hz) and 0.91 (3H, d, J=6.3 Hz). ¹³C-NMR δ(MeOD) 169.5, 141.7, 130.6,129.7, 127.4, 57.4, 47.8, 47.6, 44.2, 40.0, 39.7, 34.7, 33.8, 27.0,23.8, 22.5. IR v_(max) (ATR) 2927, 1657, 1451, 1320, 1130, 1042, 940,746, 699. ESMS=(M+Na) 405.0, (M−1) 381.0.

EXAMPLE 17

[0147]

3-(4-Benzyl-piperidine-1-sulfonyl)-octanoic acid

[0148] Yellow oil. ′H-NMR δ(MeOD) 7.44-7.13 (5H, m), 3.73-3.68 (2H, m),3.52 (1H, m), 2.90-2.77 (3H, m), 2.75-2.48 (3H, m), 2.0-1.80 (1H, m),1.80-1.17 (12H, m) and 0.91 (3H, t, J=6.7 Hz). ¹³C-NMR δ(MeOD) 174.6,141.7, 130.6, 129.7, 127.4, 59.7, 47.9, 47.6, 44.2, 39.3, 35.5, 33.7,33.1, 30.8, 227.6, 23.8, 14.7. IR v_(max) (ATR) 2923, 2853, 1709, 1451,1304, 1135, 1042, 937, 746, 699. ESMS=(M+1) 382.0, (M−1) 379.8.

EXAMPLE 18

[0149]

3-(4-Benzyl-piperidine-1-sulfonyl)-octanoic acid hydroxyamide

[0150] Yellow oil. ′H-NMR δ(MeOD) 7.28-7.13 (5H, m), 3.72-3.67 (2H, m),3.62-3.52 (1H, m), 2.96-2.76 (2H, m), 2.60-2.51 (3H, m), 2.32 (1H, dd,J=6.7, 15.4 Hz), 1.92-1.69 (1H, m), 1.69-1.18 (12H, m) and 0.91 (3H, t,J=6.7 Hz). ¹³C-NMR δ(MeOD) 169.7, 141.7, 130.6, 129.7, 127.4, 58.9,47.8, 47.5, 44.2, 39.3, 34.1, 33.8, 33.2, 30.8, 27.6, 23.8, 14.7. IRv_(max) (ATR) 2923, 2854, 1656, 1452, 1304, 1137, 1042, 938, 746, 699.ESMS=(M+1) 397.2, (M−1) 395.0, (M+TFA−1) 509.0.

[0151] In Vitro MMP Assay and Inhibitor IC₅₀ Determination

[0152] The potency of compounds of the invention as inhibitors ofcollagenase may be determined by the procedure of Cawston and Barrett,(Anal. Biochem., 99, 340-345, 1979), whereby a 1 mM solution of thecompound being tested, or a dilution thereof, is incubated at 37° for 16hours with collagen and collagenase (buffered with 25 mM Hepes, pH 7.5containing 5 mM CaCl₂, 0.05% Brij 35 and 0.02% NaN₃). The collagen isacetylated ¹⁴C collagen prepared by the method of Cawston and Murphy,(Methods in Enzymology, 80, 711, 1981). The samples are centrifuged tosediment undigested collagen, and an aliquot of the radioactivesupernatant removed for assay on a scintillation counter as a measure ofhydrolysis. The collagenase activity in the presence of 1 mM of the testcompound, or a dilution thereof, is compared to activity in a controldevoid of inhibitor and the result reported as that of inhibitorconcentration effecting 50% inhibition of the collagenase activity(IC₅₀).

[0153] The potency of compounds of the invention as inhibitors ofstromelysin may be determined by the procedure of Cawston et al,(Biochem. J., 195, 159-165, 1981), whereby a 1 mM solution of thecompound being tested, or a dilution thereof, is incubated at 37° for 16hours with stromelysin and ¹⁴C acetylate casein (buffered with 25 mMHepes, pH 7.5 containing 5 mM CaCl₂, 0.05% Brij 35 and 0.02% NaN₃). Thecasein is acetylated ¹⁴C casein prepared by the method of Cawston et al(ibid). The stromelysin activity in the presence of lmM of the testcompound, or a dilution thereof, is compared to activity in a controldevoid of inhibitor and the result reported as that of inhibitorconcentration effecting 50% inhibition of the stromelysin activity(IC₅₀).

[0154] The potency of compounds of the invention as inhibitors of 72 kDagelatinase may be determined by a procedure based on the method ofSellers et. al, Biochem. J., 171, 493-496 (1979). 72 kDa gelatinase,derived from RPMI-7951 cells is purified by gelatin-agarosechromatography. The enzyme is activated by incubation with aminophenylmercuric acetate and approximately 0.05 units is incubated with 50 kg[¹⁴C]-radiolabellet gelatin in an appropriate buffer for 16 hours at 37°C. At the end of the incubation 50 μg bovine serum albumin, togetherwith trichloroacetic acid (final concentration 16%) are added to stopthe reaction and to precipitate any undegraded substrate. The reactiontubes are placed on ice for 15 minutes before centrifugation at 10,000 gfor 15 minutes to sediment the precipitated substrate. A 200 μl aliquotof the reaction supernatant is removed and the radioactivity determinedby liquid scintillation counting. The effect of the inhibitors isdetermined by reference to a dose response curve. The IC₅₀ (theconcentration of inhibitor required to cause a 50% decrease in enzymeactivity) is obtained by fitting a curve to the data and computing theconcentration of inhibitor required to achieve 50% inhibition of theenzyme. For each IC₅₀ determination, the effect on gelatinase activityof at least 8 concentrations of the inhibitor are examined. Theinhibitors are dissolved and diluted in DMSO.

1. A compound of formula (I)

wherein X represents a carboxylic acid group —COOH, or a hydroxamic acidgroup—CONHOH; R₂ represents a radical of formula (ii)R₃—(ALK)_(m)—(Q)_(p)—(ALK)_(n)—  (II)  wherein R₃ represents hydrogen oran optionally substituted cycloalkyl, optionally substitutedcycloalkenyl, optionally substituted aryl, or optionally substitutedheterocyclic ring having 5 or 6 ring members, each ALK independentlyrepresents an optionally substituted divalent C₁-C₃ alkylene radical, Qrepresents —O—, —S—, —S(O)—, —S(O₂)—, —C(O)O—, —OC(O)— or —N(R₉)—wherein R₉ is hydrogen, C₁-C₆alkyl, or C₁-C₆alkoxy, and m, n and p areindependently 0 or 1; R₁ represents a radical of formula (II) as definedfor R₂, except that R₁ is not hydrogen; W represents a cyclic aminoradical of formula (IIIA) or (IIIB):

 wherein Y represents —O—, —S—, —S(O)—, —S(O₂)—, —N(R₈)—, —(CH(R₈))—, or—(C=N−R₈)— wherein R₈ is a radical of formula (II) as defined inrelation to R₂; and (i) R₄, R₅ R₆ and R₇ each independently represents aradical of formula (II) as defined in relation to R₂, and R_(4a) andR_(7a) each independently represent hydrogen or C₁-C₃ alkyl, or (ii) R₄,R_(4a) and R₅ taken together with the carbon atoms to which they areattached form an optionally substituted benzene or pyridine ring fusedto the cyclic amine ring, R_(7a) represents hydrogen or C₁-C₃ alkyl, andR₆ and R₇ each independently represents a radical of formula (II) asdefined in relation to R₂, or (iii) R₄, R_(4a) and R₅ taken togetherwith the carbon atoms to which they are attached form an optionallysubstituted benzene or pyridine ring fused to the cyclic amine ring, R₆,R₇ and R_(7a) taken together with the carbon atoms to which they areattached also form an optionally substituted benzene or pyridine ringfused to the cyclic amine ring, or (iv) when W is a cyclic amino radicalof formula (IIIA) wherein Y is —(CH(R₈)—, then R₄ R_(4a) and R₈ takentogether with the carbon atoms to which they are attached form anoptionally substituted benzene or pyridine ring fused to the cyclicamine ring, R_(7a) represents hydrogen or C₁-C₃ alkyl, and R₅, R₆ and R₇each independently represents a radical of formula (II) as defined inrelation to R₁ and R₂, or (v) when W is a cyclic amino radical offormula (IIIB) then R₄, R_(4a), R₇ and R_(7a)taken together with thecarbon atoms to which they are attached form an optionally substitutedbenzene or pyridine ring fused to the cyclic amine ring, and R₅ and R₆each independently represents a radical of formula (II) as defined inrelation to R₁ and R₂, or a pharmaceutically acceptable salt, hydrate orsolvate thereof.
 2. A compound as claimed in claim 1 wherein R₁ is anoptionally substituted C₁-C₆alkyl, phenyl, or phenyl(C₁-C₆alkyl)-group.3. A compound as claimed in claim 3 wherein R₁ is n-propyl, iso-propyln-butyl, iso-butyl, benzyl, phenylethyl, 4-fluorobenzyl, or4-fluorophenylethyl.
 4. A compound as claimed in any preceding claimwherein R₂ is hydrogen, or an optionally substituted C₁-C₆alkyl,phenyl(C₁-C₆alkyl)-group, or an optionally substituted heterocyclicgroup.
 5. A compound as claimed in claim 4 wherein R₂ is hydrogen,n-propyl, n-butyl, iso-butyl, benzyl, phenylethyl, tetrahydropyranyl,1-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)propyl, or1-(phthalimido)-propyl;
 6. A compound as claimed in any preceding claimwherein W is a radical of formula (IIIC), (IIID) or (IIIE)

wherein R₁₀ is as defined for R₂ in claim
 1. 7. A compound as claimed inclaim 6 wherein R₁₀ is an optionally substituted phenyl, biphenyl,phenyl(C₁-C₆alkyl)-, phenoxy, phenoxy(C₁-C₃)alkyl, or heterocyclicgroup.
 8. A compound as claimed in claim 6 wherein R₁₀ is n-propyl,n-butyl or iso-butyl; or a phenyl, phenoxy, benzyl, phenylethyl,phenylpropyl, phenoxy, or phenoxymethyl group, any of which may besubstituted in the phenyl ring, for example in the 4-position, bychloro, fluoro, methoxy or cyano; pyridinyl or pyridinyloxy either ofwhich may be substituted by chloro, fluoro, methoxy or cyano; orbiphenyl or 4-pyridinylphenyl, either of which may be substituted ineither ring by chloro, fluoro, methoxy or cyano.
 9. A compound asclaimed in claim 6 wherein W is 4-phenylmethylpiperidinyl, 4methylpiperidinyl, 4-(4-methylphenyl)piperidinyl,4-(4-chlorophenoxy)piperidinyl, 4-phenylpiperidinyl,4(4-fluorophenyl)piperidinyl, 4-(4-fluorophenoxy)piperidinyl,4-(4-pyridinyloxy)-piperidinyl, 4-(4-cyanophenyloxy)piperidinyl,4-(4-cyanophenoxyimino)-piperdinyl,4-(4′-chloro-biphenyl-4-yl)-piperdinyl, 4-(2-chloro-biphenyl-4-yl)piperdinyl, 4-(4-fluorophenylmethyl)piperidinyl,4-(4-fluorophenoxymethyl)-piperidinyl, 4-phenylpiperazinyl,4-(4-fluorophenyl)piperazinyl, 4-(4-pyridinyl-methyl)piperazinyl,4-(4-chlororophenyl)piperazinyl, 4-pyridin-4-ylpiperazinyl,4-phenylmethylpiperazinyl, or 4-(4-fluorophenylmethyl)piperazinyl. 10.3-[4-(4-Fluoro-phenoxymethyl)-piperidine-1-sulfonyl]-N-hydroxy-4-phenyl-butyramideor a pharmaceutically acceptable salt, hydrate or solvate thereof. 11.3-(4-Benzyl-piperidine-1-sulfonyl)-N-hydroxy-4-phenyl-butyramide or apharmaceutically acceptable salt, hydrate or solvate thereof.
 12. Acompound as claimed in claim 1 which is specifically named andcharacterised in any of Examples 1, 3-5, or 7-18 herein, or apharmaceutically acceptable salt, hydrate or solvate thereof.
 13. Apharmaceutical composition comprising a compound as claimed in any ofthe preceding claims, together with a pharmaceutically acceptablecarrier.
 14. A method of treatment of diseases in mammals, in particularin humans, resulting from over production of, or over responsiveness to,MMPs, which method comprises administering to the mammal an effectiveamount of a compound as claimed in any of claims 1 to 12
 15. A compoundas claimed in any of claims 1 to 12 or use in human or veterinarymedicine treatment of conditions resulting from over production of, orover responsiveness to, MMPs.
 16. The use of a compound as claimed inany of claims 1 to 12 in the preparation of an agent for treatment ofconditions in mammals, in particular in humans, resulting from overproduction of, or over responsiveness to, MMPs.
 17. A method as claimedin claim 14, or the use as claimed in claim 16 wherein the disease orcondition is rheumatoid arthritis, osteoarthritis, osteoporosis,periodontitis, gingivitis, corneal epidermal venous, diabetic or gastriculceration, ulcerative colitis, Crohn's disease, pressure sores, tumourmetastasis, invasion or growth, neuroinflammatory disorder, multiplesclerosis, psoriasis, proliferative retinopathies, neovascular glaucoma,ocular tumours, angiofibromas, hemangiomas, cardiac or cerebralinfarction, or wound healing.